Oxycodone is a semi-synthetic, μ-opioid receptor specific ligand with clear agonist properties.1 In man, oxycodone may produce any of a variety of effects including analgesia. Parenteral oxycodone was used mainly for the treatment of acute postoperative pain whereas combinations, for example oxycodone and acetaminophen, were used for moderate pain. 1 E. Kalso, Journal of Pain and Symptom Management, Volume 29, Issue, Supplement 1, May 2005, 47-56
Examples of immediate release (IR) products containing oxycodone include Percocet®, Percodan®, Roxocet®, and generic equivalents thereof. Examples of sustained-release (SR) dosage forms include Oxycontin® and generic equivalents thereof.
Oxycodone is most commonly derived from thebaine, a minor alkaloid in the papaver somniferum poppy, and from thebaine analogues prepared from codeinone. 14-Hydroxycodeinone is the immediate precursor to oxycodone in these syntheses. Thebaine can be obtained from extraction from the poppy plant papaver somniferum. However, since morphine is the major alkaloid, which accumulates in the capsules of the papaver somniferum plant, the supply of thebaine from this source is limited to some fraction of the demand for morphine. The major source of natural thebaine currently is the concentrated poppy straw (CPS) from a stably reproducing papaver somniferum plant which has been exposed to a mutagenizing agent such that the straw contains thebaine and oripavine constituting about 50% by weight or greater of the alkaloid combination consisting of morphine, codeine, thebaine and oripavine2. 2 A. J Fist, C. J. Byrne and W. L. Gerlach, U.S. Ser. No. 2004/0197428 and U.S. Pat. Nos. 6,723,894, 6,376,221, and 6,067,749
Thebaine has also been prepared by total synthesis routes, which are difficult and expensive3. Thebaine has also been prepared by the methylation of codeinone in the presence of strong base4,5 and oxidation of codeine methylether6. 3 U.S. Pat. Nos. 4,613,668 and 4,795,8134 A. Coop and K. Rice, Heterocycles, 49, 1998, 43-47.5 B. Mudryk, C. Sapino, A. Sebastian, EP 0889045 A1, U.S. Pat. No. 6,365,742 B16 R. Barber and H. Rapaport, U.S. Pat. No. 4,045,440
Purified thebaine is normally used for conversion to oxycodone but the use of thebaine CPS directly for the manufacture of oxycodone has also been disclosed7,8. 7 See claims 9 and 10 of A. J. Fist, C. J. Byrne & W. L. Gerlach, U.S. Pat. No. 6,376,221 B18 C. A. Francis, Z. Lin, C. A. Kaldahl, K. G. Antczak, V. Kumar, U.S. Pat. No. 7,071,336
Oxidation of the thebaine may alternatively be performed using potassium dichromate in acetic acid9, performic acid10, hydrogen peroxide in acetic acid9 or peracetic acid11. Improved yield, however, has been reported to be obtained by oxidizing with m-chloroperbenzoic acid in acetic acid-trifluoroacetic acid mixture12. 9 Freund et al, J. Prakt. Chem, 94, 135, (1916).10 Krassnig, Hederer, Schmidhammer, Arch. Pharm. Med. Chem., 1996, 32511 Snuperak et al., WO 2006/019364 A112 Hauser et al., J. Med. Chem., 17, 1117 (1974) and Schwartz, U.S. Pat. No. 4,795,813
14-Hydroxymorphinans have also been prepared from thebaine analogues derived from codeine without a thebaine intermediate13. 14-Hydroxycodeinone, the precursor to oxycodone, has been prepared from codeinone dienol acetate14 the ethyl dienol ether and the tert-butyl dimethylsilyl dienol ether of codeinone5. 13 Schwarz & Schwartz, U.S. Pat. No. 4,472,253 and N D Wallace, J. Med. Chem., 24, 1525-1528, 1981.14 B-S. Huang, Y. Lu, B-Y. Ji, A. S. Christodoulou U.S. Pat. No. 6,008,355
The most common method for the conversion of 14-hydroxycodeinone to oxycodone is catalytic hydrogenation using a noble metal catalyst, preferably palladium, and hydrogen gas9. Reduction of 14-hydroxycodeinone to oxycodone has also been performed using diphenylsilane and Pd(Ph3P)/ZnCl2 or with sodium hypophosphite in conjunction with a Pd/C catalyst in aqueous acetic acid.15 Oxycodone may be prepared from thebaine by: dissolution of thebaine in aqueous formic acid, oxidation treatment with 30% hydrogen peroxide16, neutralization with aqueous ammonia to yield 14-hydroxycodeinone and hydrogenation of the 14-hydroxycodeinone in acetic acid with the aid of a palladium-charcoal catalyst.17 15 F-T Chiu, Y. S. Lo U.S. Pat. No. 6,177,56716 Seki, Chem. Pharm. Bull. 18, 671-676 (1970).17 Remington's Pharmaceutical Sciences, 1041, (1975).
Oxycodone has also been prepared from thebaine bitartrate and codeinone ethyldienol ether by oxidation with hydrogen peroxide in formic acid and isopropanol, followed by catalytic hydrogenation5. Oxycodone has also been prepared by the oxidation with peracetic acid of codeinone dienol silylether in organic solvents to give 14-hydroxycodeinone, followed by catalytic hydrogenation in acetic acid solution15.
During the oxidation of thebaine to give 14-hydroxycodeinone, several by-products are formed. In particular, 7,8-dihydro-8,14-dihydroxycodeinone (DHDHC) is formed by acid catalyzed aqueous hydrolysis of 14-hydroxycodeinone as shown in Scheme 1.
